Influenza vaccination in failing hearts
Authors: Zuzana Motovska, Tobias Geisler
Journal: The Lancet Global Health (2022)

Estimates of influenza infection show that up to 1 billion people are affected each year, with up to 5 million of affected people having a severe course of illness.1Lee VJ Ho ZJM Goh EH et al.Advances in measuring influenza burden of disease.Influenza Other Respir Viruses. 2018; 12: 3-9Crossref PubMed Scopus (50) Google Scholar Influenza is persistently one of the largest challenges to global health, the economy, and society.1Lee VJ Ho ZJM Goh EH et al.Advances in measuring influenza burden of disease.Influenza Other Respir Viruses. 2018; 12: 3-9Crossref PubMed Scopus (50) Google Scholar Major cardiovascular events are an essential contributor to influenza-associated morbidity and mortality; influenza triggers cardiovascular events, and patients with a previous major cardiovascular event have a higher risk of both a major cardiovascular event recurrence and death than patients without a previous major cardiovascular event.2Yedlapati SH Khan SU Talluri S et al.Effects of influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease: a systematic review and meta-analysis.J Am Heart Assoc. 2021; 10e019636Crossref Scopus (58) Google Scholar The combination of influenza and an acute cardiovascular event demands a high level of medical care and is therefore potentially very costly. Influenza infection sets off mechanisms that result in 12% of adult patients with a hospitalisation associated with laboratory-confirmed influenza to have an episode of acute heart failure or acute ischaemic heart disease.3Chow EJ Rolfes MA O'Halloran A et al.Acute cardiovascular events associated with influenza in hospitalized adults: a cross-sectional study.Ann Intern Med. 2020; 173: 605-613Crossref PubMed Scopus (66) Google Scholar The risk of a recurrent major cardiovascular event during influenza infection is high, affecting more than one in five patients with confirmed cardiovascular disease, and more than half of these repeated events represent heart failure.4Casscells SW Granger E Kress AM Linton A Madjid M Cottrell L Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases.Circ Cardiovasc Qual Outcomes. 2009; 2: 108-115Crossref PubMed Scopus (44) Google Scholar In the initial phase of influenza, antiviral treatment mitigates the risk of recurrent cardiovascular events.4Casscells SW Granger E Kress AM Linton A Madjid M Cottrell L Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases.Circ Cardiovasc Qual Outcomes. 2009; 2: 108-115Crossref PubMed Scopus (44) Google Scholar However, in patients who are hospitalised with an acute event, treatments that can reverse the risk of a more severe scenario are missing even when the influenza infection is identified early. Evidence shows that influenza vaccination reduces major cardiovascular events in patients with coronary artery disease, and has an even larger effect on patients who have been recently diagnosed with acute coronary syndrome, in whom one cardiovascular death is prevented for every 36 vaccinated patients.5Behrouzi B Bhatt DL Cannon CP et al.Association of influenza vaccination with cardiovascular risk: a meta-analysis.JAMA Netw Open. 2022; 5e228873Crossref PubMed Scopus (28) Google Scholar Moreover, this benefit is not reduced or offset by the risk of serious adverse events that are linked to the flu vaccine. Patients with heart failure are well positioned to benefit from the influenza vaccine, regardless of categorisation by left ventricular function. During influenza outbreaks, the likelihood of hospitalisation rises substantially in patients with heart failure,6Sandoval C Walter SD Krueger P et al.Risk of hospitalization during influenza season among a cohort of patients with congestive heart failure.Epidemiol Infect. 2007; 135: 574-582Crossref PubMed Scopus (39) Google Scholar and the accumulation of hospital admissions is associated with an increased risk of death. Influenza has long been recognised as an independent predictor of mortality, adverse clinical outcomes, and increased length of stay for patients with an infection-induced heart failure hospitalisation.7Panhwar MS Kalra A Gupta T et al.Effect of influenza on outcomes in patients with heart failure.JACC Heart Fail. 2019; 7: 112-117Crossref PubMed Scopus (52) Google Scholar With the exponentially growing prevalence of heart failure, which already affects 26 million people worldwide,8Savarese G Lund LH Global public health burden of heart failure.Card Fail Rev. 2017; 3: 7-11Crossref PubMed Google Scholar and the annual outbreaks of seasonal influenza, vaccination of patients with heart failure is projected to have an enormous positive impact. It is therefore surprising that, despite the logical deductions, the certainty of the available evidence documenting the benefit of the influenza vaccine in patients with heart failure, based on meta-analyses of non-randomised studies, is low or very low,9Gupta C Sachdeva A Khamar J Bu C Bartoszko J Loeb M Effectiveness of the influenza vaccine at reducing adverse events in patients with heart failure: a systematic review and meta-analysis.Vaccine. 2022; 40: 3433-3443Crossref PubMed Scopus (4) Google Scholar as most outcomes in the included studies had a severe risk of bias.10Rodrigues BS David C Costa J Ferreira JJ Pinto FJ Caldeira D Influenza vaccination in patients with heart failure: a systematic review and meta-analysis of observational studies.Heart. 2020; 106: 350-357Crossref PubMed Scopus (39) Google Scholar The IVVE (Influenza Vaccine to Prevent Adverse Vascular Events) trial11Loeb M Roy A Dokainish H et al.Influenza vaccine to reduce adverse vascular events in patients with heart failure: a multinational randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2022; 10: e1835-e1844Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar by Mark Loeb and colleagues, published in the Lancet Global Health, is the first multinational randomised, double-blind, placebo-controlled study testing the effect of a standard dose influenza vaccine on outcomes in patients with heart failure. The study was implemented in ten low-income and middle-income countries in Asia, the Middle East, and Africa (40% of enrolled patients were in Africa). To meet the main inclusion criterion, the definition of heart failure was based on clinical symptoms corresponding to stages II, III, or IV of the New York Heart Association functional classification of heart failure. There were 5129 enrolled participants (51·4% of whom were women), with a mean age of 57·2 years; 2560 participants received an inactivated standard-dose influenza vaccine and 2569 participants received a placebo. The representation of patients with previous myocardial infarction was 20·7%, and 8·0% had had a previous stroke, which was balanced in both compared study groups. Of the causes of heart failure, 29·8% were due to coronary ischaemia and 38·4% were attributed to hypertension. The vaccine was administered annually for three influenza seasons, and the mean follow-up duration was 2·3 (SD 0·9) years. The study failed to confirm a significant impact of the influenza vaccine on the occurrence of the two co-primary outcomes, the first being defined as the time to the first occurrence of the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke; and the second being a recurrent event composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and heart failure leading to hospitalisation. The event rates of non-fatal myocardial infarction, a component of the co-primary outcomes, were very low (0·8% and 0·9%). However, the vaccine significantly reduced the secondary outcomes of all-cause hospitalisation by 16%, which was mainly due to a reduction in the rate of heart failure hospitalisation, and a 42% reduction in the rate of community-acquired pneumonia. In the prespecified analysis, in which events were limited to periods of peak influenza circulation, the first primary outcome (hazard ratio [HR] 0·82 [95% CI 0·68–0·99]), all-cause death (0·79 [0·66–0·95]), and pneumonia (0·51 [0·32–0·81]) were all lower in the influenza vaccinated group. In some countries in Africa, influenza circulates throughout the year; nevertheless, peak influenza transmission periods were determinable. Regarding safety, there were no serious adverse events in the immediate post-vaccination period, and no adverse events were severe enough to cause discontinuation of the trial. Loeb and colleagues are to be commended for designing an important study, even with its declared limitations, which can be also attributed to the definition of primary outcomes in relation to the target heart failure population (29·8% with an ischaemic cause of heart failure). The opportunity to add to the evidence on the benefits of the influenza vaccine compared with placebo is challenging in countries with extremely low vaccination coverage and a high prevalence of at-risk populations. The exceptional representative proportion of enrolled women is an indisputable positive of the study. The study adds further weight to implementing the influenza vaccine as a foundational element of therapy in patients with cardiovascular disease. It is impossible to ignore the documented benefits of the influenza vaccine, which is associated with little potential to cause severe harm and negligible costs compared with influenza-related major cardiovascular events hospital care. The time is ripe to eliminate unjustified prejudices against this effective treatment and stop the shifting responsibility for influenza vaccination—the responsibility lies with every specialist managing cardiovascular disease patient care. We declare no competing interests. Influenza vaccine to reduce adverse vascular events in patients with heart failure: a multinational randomised, double-blind, placebo-controlled trialAlthough the prespecified co-primary outcomes during the entire period of observation were not statistically significant, the reduction during the peak influenza circulating period suggests that there is likely to be a clinical benefit of giving influenza vaccine, given the clear reduction in pneumonia, a moderate reduction in hospitalisations, and a reduction in cardiovascular events and deaths during periods of peak circulation of influenza. Taken in conjunction with previous trials and the observational studies, the collective data suggest benefit. Full-Text PDF Open Access